Crystal forms of n-(trans-4-isopropylcyclohexylcarbonyl)-d-phenylalanine

ABSTRACT

New crystal forms of N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine, also known as nateglinide, may be produced by dissolving nateglinide in any of its forms, including solvates, in an organic solvent to form a solution followed by precipitation of nateglinide from the solution, and isolating and drying the precipitated crystal form of nateglinide. The precipitation of nateglinide may be induced either by cooling the solution, or by addition of another solvent which is miscible with the first solvent but in which nateglinide is only poorly soluble, or by combination of the two. Depending on the solvent a specific crystal form of nateglinide may be obtained, e.g., the R′-type crystal form of nateglinide produced by the described method has a different melting point, infra red spectra and X-ray diffraction patterns from the previously known crystal forms of nateglinide.

The present invention relates to methods for the production of differentcrystal forms ofN-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine, also known asnateglinide. In particular, the invention relates to forming crystals ofnateglinide referred to herein as the R′-type crystals or crystal formof nateglinide.

Nateglinide of formula (I) is a known substance having therapeuticutility in depressing blood glucose levels.

Nateglinide is disclosed in U.S. Pat. No. 4,816,484, the entire contentsof which are expressly incorporated herein by reference.

Nateglinide is known to have several crystal forms. Examples of suchcrystal forms include the forms known as B-type and H-type crystals. TheB-type and H-type crystals and methods for their production aredescribed in U.S. Pat. No. 5,463,116, the entire contents of which areincorporated herein by reference.

According to one aspect of the instant invention herein is provided amethod for the production of different crystal forms of nateglinidewherein the method comprises dissolving nateglinide in any of its forms,including solvates such as hydrates, methanolates, ethanolates andacetonates, in a solvent including mixed solvents, forming thenateglinide crystals, isolating and drying the precipitated crystal formof nateglinide.

In one embodiment of the instant invention, R′-type crystal form ofnateglinide can be produced by a method wherein the method comprisesdissolving nateglinide in a solvent in which nateglinide is readilysoluble at an ambient temperature to form a solution, treating thesolution with another solvent which is miscible with the first solvent,and in which nateglinide is only poorly soluble to induce precipitationof the R′-type crystals of nateglinide, isolating and drying theprecipitated crystal form of nateglinide, including solvates such ashydrates, methanolates, ethanolates and acetonates.

Other objects, features, advantages and aspects of the present inventionwill become apparent to those skilled in the art from the followingdescription, appended claims and accompanying drawings. It should beunderstood, however, that the following description, appended claims,drawings and a specific example while indicating a preferred embodimentof the invention, are given by way of illustration only. Various changesand modifications within the spirit and scope of the disclosed inventionwill become readily apparent to those skilled in the art from readingthe following.

FIG. 1 shows a powder X-ray diffraction pattern of B-type crystals ofN-(trans-4-isopropyl-cyclohexylcarbonyl)-D-phenylalanine;

FIG. 2 shows an infra red absorption spectrum of B-type crystals ofN-(trans-4-isopropyl-cyclohexylcarbonyl)-D-phenylalanine;

As indicated, one embodiment of the instant invention providesnateglinide in R′-type crystal form. Examples of the physical propertiesof the B-type and the R′-type crystal form of nateglinide are asfollows:

The melting point (mp) of B-type nateglinide crystals has been measuredby the DSC method to be in the range of 128 to 131° C.

An example of a melting point of the R′-type crystal form of nateglinideas measured by the DSC method has been found to be about 108° C.

An example of the powder X-ray diffraction patterns of the B-typecrystal form of nateglinide may be found in FIG. 1. The diffractionpattern of the B-type crystal form of nateglinide shows maxima at 2θvalues of 3.9, 5.0, 5.2 and 14.1.

An example of an infrared absorption spectrum of B-type crystal form ofnateglinide, obtained by a KBr method is shown in FIG. 2. The infraredabsorption spectrum of the B-type crystal form of nateglinide ischaracterized by absorptions at around 3291, 2955, 1737, 1642 and 1210cm⁻¹.

As summarized above, one aspect of the instant invention provides amethod for the production of different crystal forms of nateglinidewherein the method comprises dissolving nateglinide in any of its forms,including solvates such as hydrates, methanolates, ethanolates andacetonates, in a solvent which includes mixed solvents, forming thenateglinide crystals, isolating and drying the precipitated crystal formof nateglinide.

In one embodiment, R′-type crystal form of nateglinide can be producedby a method wherein the method comprises dissolving nateglinide in asolvent, referred to herein as a first solvent, in which nateglinide isreadily soluble at an ambient temperature to form a solution, treatingthe solution with another solvent, referred to herein as a secondsolvent, which is miscible with the first solvent and in whichnateglinide is only poorly soluble, to induce precipitation of theR′-type crystals of nateglinide, isolating and drying the precipitatedcrystal form of nateglinide, including solvates such as hydrates,methanolates, ethanolates and acetonates.

First solvents in which nateglinide is readily soluble, i.e., in amountsof at least 1% by weight at an ambient temperature, include loweralcohols, such as methanol, ethanol and isopropanol. Polar solvents suchas acetone, tetrahydrofuran, dioxane and dichloromethane can also beeffective when used as the first solvent. Second solvents in whichnateglinide is only poorly soluble, i.e., in amounts of 0.01% by weightor less, include water, hexane, heptane and diethyl ether. Where a mixedsolvent is employed as the first solvent, a mixture of ethanol andtoluene or a mixture of methanol and ethyl acetate is effectivepreferably in combination with water as the second solvent, and morepreferably with water containing from about 0.5 to about 3% by weight ofhydroxypropylmethylcellulose. The amount of nateglinide in the solventranges preferably from 1 to 50% by weight of the resulting mixture. Ifthe amount of nateglinide is more than 50% by weight then the slurryproperties of the initial suspension are poor and it will be difficultto agitate the mixture and dissolve the solid. On the other hand, it isnot efficient in terms of the volume of the solvent required to use lessthan 1% of nateglinide by weight. The ambient temperature, i.e., thetemperature in which nateglinide is dissolved in the first solvent,ranges preferably from room temperature to about the boiling point ofthe solvent, and more preferably from room temperature to about 70° C.The amount of nateglinide dissolved in the first solvent rangespreferably from 5 to 40% by weight of the resulting solution. Thesolution of nateglinide in the first solvent may be added to the secondsolvent, or the second solvent may be added to the solution ofnateglinide in the first solvent. The ratio of the first solvent to thesecond solvent in the resulting mixture ranges preferably from about 1to 3 to about 1 to 9 by volume. It may be advantageous to add seedcrystals, preferably B-type nateglinide seed crystals, in the mixture toaid precipitation of the desired crystal form of nateglinide. Theresulting mixture containing nateglinide may be stirred or cooled to alower temperature for a time sufficient to assure complete precipitationof the desired nateglinide crystals.

Conventional methods, such as heating and stirring, may be used fordissolution of nateglinide. Nateglinide in any of its forms, includingsolvates such as hydrates, methanolates, ethanolates and acetonates, maybe added to the solvent or the solvent may be added onto nateglinide,stirred, and heated to an ambient temperature ranging from roomtemperature to about the boiling point of the solvent to form asolution. Stirring, cooling and addition of seed crystals may be used tofurther induce precipitation of the desired crystal form of nateglinide.The precipitated crystals may be isolated by conventional methods, suchas vacuum filtration or centrifugation. The crystals may be washed,preferably with a solvent or a solvent mixture consisting of solventsused in the crystallization. During isolation and washing, cooling maybe applied, if so desired, preferably cooling the crystals to atemperature ranging from about 20 to about 0° C. The isolatednateglinide crystals may be dried under atmospheric or reduced pressure,preferably under reduced pressure ranging from about 20 to about 0.1mmHg, at a temperature ranging from room temperature to about 80° C.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising crystals as obtainable by the above method, inparticular the R′-type crystals, and pharmaceutically acceptableexcipients, diluents or carriers thereof.

In a further aspect, the present invention provides a method formanufacture of a pharmaceutical composition comprising mixing aneffective amount of crystals as obtainable by the method of the firstaspect of the present invention, in particular the R′-type crystals, andpharmaceutically acceptable excipients, diluents or carriers thereof.

In a still further aspect, the present invention provides a method fortreatment of a human or another mammal to depress its blood glucoselevel comprising administering an effective amount of nateglinidecrystals as obtainable by the method of the present invention, inparticular the R′-type crystal form.

The present invention is further described by the following example. Theexample is provided solely to illustrate the invention by reference tospecific embodiment. This example, while illustrating certain specificaspects of the invention, do not portray the limitations or circumscribethe scope of the disclosed invention.

EXAMPLE

The R′-type nateglinide crystals may be prepared as follows:

The H-type nateglinide crystals are dissolved in a mixture of ethanoland toluene (50% of ethanol and 50% of toluene by volume; 160 mg ofnateglinide/mL) at room temperature while stirring. After all the solidsare dissolved, water containing 1% hydroxypropylmethylcellulose is addedto induce precipitation (about 7× the volume of ethanol-toluene used).After stirring for 2 h further, the precipitated solids are collected byvacuum filtration, washed and dried overnight at 50° C. under reducedpressure to afford the R′-type crystals: mp 108° C.

Although the present invention has been described in considerable detailwith reference to certain preferred versions thereof, other versions arepossible without departing from the spirit and scope of the preferredversions contained herein. All references and Patents (U.S. and others)referred to herein are hereby incorporated by reference in theirentirety as if set forth in full herein.

1. A crystal form of nateglinide having a melting point of about 108°C.; or solvates thereof.
 2. A method for the production of R′-typecrystal form of nateglinide wherein the method comprises; (a) dissolvingnateglinide in any of its forms in a first solvent in which nateglinideis readily soluble at an ambient temperature to form a solution; (b)treating the solution with a second solvent which is miscible with thefirst solvent, and in which nateglinide is only poorly soluble to induceprecipitation of R′-type crystals of nateglinide; and (c) isolating anddrying the precipitated crystal form of nateglinide.
 3. The method ofclaim 2, wherein the precipitation of the crystal form of nateglinide isinduced by stirring, cooling or by adding seed crystals of nateglinide.4. The method of claim 2, wherein the ambient temperature ranges fromroom temperature to the boiling point of the solvent.
 5. The method ofclaim 2, wherein the crystal form of nateglinide is dried underatmospheric or reduced pressure at a temperature ranging from roomtemperature to 70° C.
 6. The method of claim 2, wherein the firstsolvent is a mixture of ethanol and toluene.
 7. The method of claim 6,wherein the second solvent is water containinghydroxypropylmethylcellulose.
 8. The method of claim 7, wherein thefirst solvent contains 50% of ethanol by volume; the second solventcontains 1% of hydroxypropylmethylcellulose; and the ratio of the firstsolvent to the second solvent is 1 to 7 by volume.
 9. The method ofclaim 8, wherein the ambient temperature is room temperature; and thecrystal form of nateglinide is dried under reduced pressure at atemperature ranging from room temperature to 50° C.